Soluble guanylate cyclase (sGC) is an enzyme which produces cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP), and which consists of a dimer of α subunit and β subunit. The β subunit binds heme, and the iron coordinated to the heme generally interacts with the histidine residue as 105th amino acid to have an inactivated structure. Nitrogen monoxide (NO) is known to be an major sGC stimulating factor in vivo, and according to interaction with the heme iron which is present in β subunit of sGC and dissociating the interaction between the heme iron and the histidine residue of β subunit, it promotes conversion into activated form. cGMP produced by activated sGC subsequently activates, for example, a protein kinase, or an ion channel to play various roles including relaxing vascular smooth muscle, suppressing platelet activation, suppressing cell proliferation, and olfactory neuronal transmission. Under pathological condition, activity of sGC is lowered and decomposition of sGC occurs to suppress the cGMP system, thus leading to contraction of, for example, vascular smooth muscle, activation of platelet, or cell proliferation. Eventually, it may cause, for example, hypertension, pulmonary hypertension, heart failure, endothelial function disorder, atherosclerosis, peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction, or renal function disorder (Non Patent Documents 1 and 2).
For activating sGC, nitrates such as nitroglycerin are widely used in clinical use. They induce the activation of sGC by supplying exogenous NO, and thus exhibit a pharmaceutical effect. However, the nitrate agents are known to have a tolerance in addition to side effects, which is a significant problem of the pharmaceutical agent. It has been suggested that the tolerance to the nitrate agents are based on a mechanism such as reduced activity of mitochondrial aldehyde dehydrogenase involved with NO release, which is different from sGC (Non Patent Document 3). Thus, a compound directly activating sGC without being related to NO release can avoid the tolerance. Further, under disease state such as aging, hypertension, diabetes, or hyperlipidemia, it has been shown that oxidation of heme iron or decomposition of heme is enhanced by oxidative stress to prevent the interaction between NO and heme, and thus it cannot be expected to have sufficient activation of sGC (Non Patent Document 4). As an sGC stimulating agent other than NO, a heme-dependent direct sGC stimulating agent represented by Riociguat (Patent Document 1) is known. Those compounds can activate sGC independing on NO, however, it is described that they cannot fully exhibit the sGC activating property under condition for oxidizing heme iron (Non Patent Document 5). Thus, unlike NO or Riociguat, a compound having a function of directly activating sGC without depending on oxidation state of heme is believed to be effective for treatment or prevention of various disorders such as hypertension, pulmonary hypertension, heart failure, endothelial function disorder, atherosclerosis, peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction, and renal function disorder.
As a compound having a function of directly activating sGC without depending on oxidation state of heme, Cinaciguat and derivatives thereof are disclosed in Patent Document 2, pyrazole, triazole derivatives are disclosed in Patent Document 3, 2,6-disubstituted pyridine derivatives are disclosed in Patent Document 4, and heterocyclic derivatives are disclosed in Patent Document 5.